Discovery of a novel azetidine scaffold for colony stimulating factor-1 receptor (CSF-1R) Type II inhibitors by the use of docking models

Article abstract of DOI:10.1016/j.bmcl.2018.10.051

We report the discovery of a novel azetidine scaffold for colony stimulating factor-1 receptor (CSF-1R) Type II inhibitors by using a structure-based drug design (SBDD) based on a docking model. The work leads to the representative compound 4a with high C

Full text of DOI:10.1016/j.bmcl.2018.10.051

Accepted Manuscript
Discovery of a novel azetidine scaffold for colony stimulating factor-1 receptor
(CSF-1R) Type II inhibitors by the use of docking models
Kazutaka Ikegashira, Taku Ikenogami, Takayuki Yamasaki, Yasunori Hase,
Takayuki Yamaguchi, Koji Inagaki, Satoki Doi, Tsuyoshi Adachi, Yoshihisa
Koga, Hiromasa Hashimoto
PII:
S0960-894X(18)30852-7
https://doi.org/10.1016/j.bmcl.2018.10.051
BMCL 26110
DOI:
Reference:
Bioorganic & Medicinal Chemistry Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
20 August 2018
24 October 2018
30 October 2018
Please cite this article as: Ikegashira, K., Ikenogami, T., Yamasaki, T., Hase, Y., Yamaguchi, T., Inagaki, K., Doi,
S., Adachi, T., Koga, Y., Hashimoto, H., Discovery of a novel azetidine scaffold for colony stimulating factor-1
receptor (CSF-1R) Type II inhibitors by the use of docking models, Bioorganic & Medicinal Chemistry Letters
(2018), doi: https://doi.org/10.1016/j.bmcl.2018.10.051
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Discovery of a novel azetidine scaffold for
colony stimulating factor-1 receptor (CSF-
1R) Type II inhibitors by the use of docking
models
Leave this area blank for abstract info.
Kazutaka Ikegashira*, Taku Ikenogami, Takayuki Yamasaki, Yasunori Hase, Takayuki Yamaguchi, Koji
Inagaki, Satoki Doi, Tsuyoshi Adachi, Yoshihisa Koga, Hiromasa Hashimoto
O
O
HO
N
O
O
N
4a
CSF-1R IC50 = 9.1 nM

Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com
Discovery of a novel azetidine scaffold for colony stimulating factor-1 receptor
(CSF-1R) Type II inhibitors by the use of docking models
Kazutaka Ikegashira*, Taku Ikenogami, Takayuki Yamasaki, Yasunori Hase, Takayuki Yamaguchi, Koji
Inagaki, Satoki Doi, Tsuyoshi Adachi, Yoshihisa Koga, Hiromasa Hashimoto
Central Pharmaceutical Research Institute, Japan Tobacco Inc., 1-1, Murasaki-cho, Takatsuki, Osaka 569-1125, Japan
ARTICLE INFO
ABSTRACT
Article history:
Received
Revised
Accepted
Available online
We report the discovery of a novel azetidine scaffold for colony stimulating factor-1 receptor
(CSF-1R) Type II inhibitors by using a structure-based drug design (SBDD) based on a docking
model. The work leads to the representative compound 4a with high CSF-1R inhibitory activity
(IC50 = 9.1 nM). The obtained crystal structure of an azetidine compound with CSF-1R, which
matched our predicted docking model, demonstrates that the azetidine compounds bind to the
DFG-out conformation of the protein as a Type II inhibitor.
Keywords:
cFMS
CSF-1R
2009 Elsevier Ltd. All rights reserved.
DFG-out
Type II inhibitor
Azetidine scaffold
Colony-stimulating factor-1 receptor (CSF-1R or cFMS) is a
type III receptor tyrosine kinases that is generally expressed at
myeloid cells in the mononuclear phagocyte system and at
progenitor cells in bone marrow.1 It binds to CSF-1, known as
macrophage colony-stimulating factor (M-CSF).2 Also,
interleukin-34 (IL-34) has recently been reported as another
ligand.3 The binding to CSF-1 and IL-34 activates the receptor
kinase through a process of dimerization and subsequent
autophosphorylation. The activation stimulates differentiation,
proliferation, survival and migration of monocyte-macrophage
lineage cells.1,4 Also, macrophages produce inflammatory
mediators such as interleukin and lymphokine, and lead to
differentiation, proliferation and activation of a variety of
immune cells. These immune cells are also involved in the
pathological conditions of rheumatoid arthritis (RA) and multiple
sclerosis.
Functional states of a typical protein kinase seem to be
characterized by the conformation of the DFG (Asp-Phe-Gly)
motif, which are conserved among most of protein kinases and
located in the activation loops. The majority of inhibitors, which
are well known as Type I inhibitors, target the ATP-binding site
of the kinase with the DFG-in conformation as its active state. On
the other hand, Type II inhibitors (e.g., imatinib and sorafenib)
induce the DFG-out conformations, and occupy an additional
hydrophobic pocket created by this rearrangement.12 With more
favorable kinase selectivity and slower off-rates, Type II
inhibitors are expected to possess several advantages over Type I
inhibitor.
We have discovered a new class of azetidine compounds as
selective CSF-1R Type II kinase inhibitors and our work led to
the identification of JTE-952,13 which is a clinical candidate with
cellular and in vivo potency. Herein, we report the discovery of
this azetidine scaffold.
In addition, this signaling promotes differentiation of
osteoclastic precursors into mature osteoclasts.4 Osteoclasts,
whose formation requires the presence of a receptor activator of
nuclear factor ligand kB (RANK) and CSF-1, promote bone
destruction and bone absorption and play a key role in
osteoporosis as well as deformity in RA. Therefore, inhibition of
CSF-1R signaling is expected to be therapeutic in RA. This
hypothesis is supported by the biological studies conducted with
op/op mice which are missing endogenous CSF-1. In addition, a
number of CSF-1R inhibitors with in vivo anti-inflammatory
efficacy have been reported in the literature, including Ki20227,5
GW2580,6a-c JNJ-28312141,7 Arry382,8 BLZ945,9 AZD7507,10
and PLX-3397.11
Although several selective CSF-1R inhibitors have been
reported, GW2580 is one of the most selective inhibitors for
CSF-1R.6a-d It shows no inhibition of 186 other kinases, except
for TrkA. The co-crystal structure of GW2580 with CSF-1R
showed that GW2580 is a typical Type II inhibitor, which binds
to the DFG-out state protein, as shown in Fig. 1. 6b,c, 14 Ring A
binds to the hinge region of the kinase protein with four
hydrogen bonds. The rings A and B form an L-shape
conformation through methylene. The two oxygen atoms of the
methoxy and benzyloxy groups on ring B make the bidentate
hydrogen bonding network to the backbone amide NH of G796,
and ring C occupy the hydrophobic pocket in the DFG-out state.

We hypothesized that the unique L-shape conformation and the
bidentate hydrogen bonds are important features for Type II
inhibitors of CSF-1R. We planned to alter the hinge binding
substructure to increase the activity while maintaining the
bidentate hydrogen bonds, which are composed of methoxy and
benzyloxy groups, for the Type II inhibitor.
instead of the azetidine ring. These compounds did not show
activity as we had predicted (data not shown in this report).
Table 1. CSF1R Enzyme Assay a IC50 Values for compounds 1a-
d, 2a-b, and 3a-b.
R
N
Fig. 1 The co-crystal structure of GW2580 and CSF-1R reported
O
O
in US2004/0002145.a
comp
R
CSF1R IC50
62 nM
O
O
N
1a
1b
1c
1d
2a
2b
3a
3b
510 nM
N
NH2
N
B
A
N
O
H2N
O
C
O
1100 nM
430 nM
O
N
GW2580
a
Nitrogen, oxygen, and sulfur atoms are shown in blue, red, and orange,
O
respectively. Hydrogen bonds between the compound and protein are shown
as yellow dashed lines.
Initially, we expected that the binding of saturated rings such
as azetidine, pyrrolidine, and piperidine directly to ring B could
produce the L-shaped conformation similar to GW2580. We
anticipated that the azetidine structure would be the most
promising. The azetidine scaffold particularly overlapped with
the GW2580 active conformation without a collision against the
protein (data not shown in this report), while the pyrrolidine and
piperidine compounds did collide with the protein. Therefore, we
focused our search on compounds based on the azetidine
structure with the methoxy and benzyloxy substituents on ring B
to preserve the kinase selectivity.
N
>3000 nM
>3000 nM
>3000 nM
1400 nM
N
N
We began exploring azetidine analogues by using pyridine
rings to identify the appropriate position of the hydrogen bond
acceptor that would interact with the hinge region since it is well
known that kinase hinge binders must have at least a hydrogen
bond acceptor. Compounds 1a-d, 2a-b, and 3a-b were
synthesized and tested in the CSF-1R enzyme assay (Table 1). In
this study, we used the 4-ethyl-benzyloxy substituent instead of
4-methoxy-benzyloxy because our preliminary studies showed
that this substituent had equivalent activity and greater chemical
stability. The 2-picolylamide analogue (1a) showed the best
activity, which was equivalent to GW2580, making it the
optimum compound among the amide analogues (1b-d).
Surprisingly, the benzoyl substituent, not the pyridine ring,
showed medium activity. The pyridylmethyl analogues (2a-b)
and the direct pyridine rings molecules (3a-b) had little or no
activity. Thus, the amide analogues did not require the pyridine
ring, but rather, a planar structure and the carbonyl seemed to
serve as a hydrogen bond acceptor. Also, to verify the structural
determinants, we prepared and evaluated pyrrolidine analogues
N
a
Human CSF-1R (amino acids 538 – 972) encompassing the tyrosine kinase
domain (obtained in-house) was used. For details, see the Supporting
Information.
To gain insights into the mechanism of action, we modeled the
binding mode of compound I based on the co-crystal structure of
GW2580. The result of this docking study is shown in Fig. 2.14,15
We were surprised to observe that the acceptor for hydrogen-
bonding to the backbone NH of Cys666 was not the N-atom in
pyridine, but rather the O-atom in C=O. Also, the conformation

of the 2-picolyl - azetidine amide moiety was perfectly planar
and the position between C=O vs. C=N in the pyridine was anti
(i.e., anti-planar conformation). We thought that an electrostatic
repulsion interaction between the C=O and the N-atom in
pyridine was the main factor. Therefore, contrary to our
assumption, the N-atom in pyridine was required, but not as a
hydrogen bond acceptor, but rather for stabilizing the anti-planar
conformation of the 2-picolyl-amide structure.
Table 2. CSF1R Enzyme Assay a IC50 Values for compounds 1e-
h and 4a-b
O
Py
N
O
O
comp
Py
CSF1R IC50
2216 nM
Fig. 2 The Docking Model of compound I.a
1e
1f
N
N
41 nM
86 nM
145 nM
9.1 nM
25 nM
1g
1h
4a
4b
N
N
O
N
N
O
O
O
I
O
HO
The electrostatic repulsion interaction
N
N
a
Nitrogen, oxygen, and sulfur atoms are shown in blue, red, and orange,
respectively. Hydrogen bonds between the compound and protein are shown
as yellow dashed lines.
HO
O
Next, we investigated the optimal direction to orient the
compound toward the outside of the protein to increase the
enzyme inhibition. From our docking model, we predicted that
we could locate substituents at the 4-, 5-, 6-positions on the
pyridine ring toward the outside of the protein and the 4-position
specifically would be the best position. To confirm this idea, we
synthesized compounds 1e-h and 4a-b and tested them in the
CSF-1R enzyme assay (Table 2). Initially, we examined the
methyl group on the pyridine ring. The IC50 values of the 4-
methyl analogue (1f, IC50 = 41 nM) was best and also the 5-
methyl compound (1g, IC50 = 86 nM) showed inhibition of the
10-8 M order, whereas the 6-methyl (1h, IC50 = 145 nM) and 3-
methyl (1e, IC50 = 2216nM) derivatives led to reduced activity.
To confirm the best position, we also introduced ethylene glycol
unit at the 4- and 5-positions. We predicted that the alcohol unit
would increase activity and hydrophilicity by extending the
molecule toward the outside of the protein. The 4-(hydroxy-
ethoxy)-pyridine derivative 4a showed the best IC50 (9.1 nM). 5-
(Hydroxyethoxy)-pyridine derivative 4b led to approximately a
3-fold decrease in biochemical activity (IC50 = 25 nM) compared
to 4a. These results were consistent with our prediction based on
the docking model.
a
Human CSF-1R (amino acids 538 – 972) encompassing the tyrosine kinase
domain (obtained in-house) was used. For details, see the Supporting
Information.
The syntheses of compounds in this study were accomplished
as shown in Scheme 1.
The syntheses of 1a-j, 2a-b, 3a-b, and 4a-b were started from
4-iodo-2-methoxyphenol 5. The phenol 5 was benzylated with 4-
ethyl-benzylchloride 6 in the presence of K2CO3 in N,N-
dimethylformamide (DMF) to give 1-benzyloxy-4-iodo-2-
methoxybenzene derivatives 7. Negishi coupling of 7 with
azetidinyl
bis(triphenylphosphine)palladium (II) chloride or Pd(OAc)2 and
Sphos (dicyclohexyl-(2’6’-dimethoxy-[1,1’-biphenyl]-2-
yl)phosphine) as the catalyst provided the N-Boc-3-phenyl-
azetidine 10. The yields using the catalyst of Pd(OAc)2 and
Sphos were higher than with bis(triphenylphosphine)palladium
(II) chloride. The azetidinyl zincate was prepared by N-Boc-3-
iodo-azetidine 8 and zinc in the presence of lithium chloride in
N,N-dimethylacetamide (DMA). Removal of the Boc protective
group from 10 with methanesulfonic acid (MsOH) in ethanol or
2-propanol gave azetidine methanesulfonic acid salt 11 as a key
intermediate. In this deprotection, the usage of HCl as an acid
provided lower yields compared to MsOH because of opening of
the azetidine ring by HCl (the results are not shown in this report).
Condensation of 11 with the corresponding carboxylic acid 12
zincate
reagent
9
using

afforded the azetidine-amide derivatives 1. Alkylation of 11 with
the corresponding pyridylmethyl chloride 13 afforded 2. Pd-
mediated amination, using Pd(OAc)2 and BINAP as catalyst and
Cs2CO3 as base, of 11 with the corresponding pyridyl halide 14
led to 3.
the protein and is stabilized by a hydrogen bond network with
bulk water molecules.
The crystal structure indicated that we attained our aim of
generating a novel scaffold for a CSF-1R Type II inhibitor.
4a-b were obtained by alkylations of 1i,
bromoethanol in the presence of K2CO3 in DMF.
j
with 2-
Fig. 3 The co-crystal structure of JTE-952 with CSF-1R.a
Scheme 1.
Boc
Boc
N
I
8
b
I
O
O
I
O
a
c
HCl
N
OH
ZnI•LiCl
5
6
7
9
MsOH
O
Boc
HN
N
O
d
O
O
10
11
O
N
N
O
O
O
Ar
N
e
O
11
Ar COOH
O
JTE-952
12
O
1
OH
OH
Py
N
a
Nitrogen, oxygen, and sulfur atoms are shown in blue, red, and orange,
O
f
11
11
respectively. DFG(Asp-Phe-Gly) motif are shown in pink. Hydrogen bonds
between the compound and protein are shown as yellow dashed lines.
Py
Cl
O
13
2
Py
N
O
g
In conclusion, we have described the discovery of a new class
azetidine compounds as CSF-1R Type II inhibitors. We designed
the azetidine scaffold based on the crystal structure of GW2580.
We synthesized and assayed the azetidine compounds and also
obtained the crystal structure of our compound and the CSF-1R
protein. Our results allowed us to identify a novel scaffold with
great therapeutic potential. Further efforts to improve cellular
activity and in vivo efficacy will be described in the next report.
Py Br
O
14
3
O
O
N
N
N
N
O
O
O
O
HO
f
HO
O
Br
15
4a, b
OH
1i, j
Acknowledgments
Reagents and conditions: (a) K2CO3, DMF, rt; (b) Zn, dibromoethane, LiCl,
DMA, rt; (c) PdCl2(PPh3)2 or Pd(OAc)2 and Sphos, DMA, rt; (d) MsOH,
EtOH or IPA, 80 °C; (e) WSC•HCl, HOBt•H2O, Et3N, DMF, rt; (f) K2CO3,
DMF, 80 °C; (g) Pd(OAc)2, BINAP, Cs2CO3, 1,4-dioxane, 80 °C.
We thank Mr. Eita Nagao for analytical support, Ms. Reina
Kakefuda and Dr. Naoki Miyagawa for running the biological
assays. We also thank Dr. Tetsuo Yamashita and Dr. Michiko
Aoki for assistance with the synchrotron data collection. We are
grateful to Mr. Tatsuya Matsumoto, Mr. Takuya Matsuo, Mr.
Naoki Ogawa, Dr. Atsushi Hagiwara, and Dr. Takahiro Oka for
support.
To confirm our design, we attempted to obtain crystal
structures of our azetidine series compounds in complex with
CSF-1R. We obtained a crystal structure at 1.8Å resolution of
JTE-952,16 which is our clinical candidate and is described in
detail in our next report. The enzyme-bound bioactive
conformation was almost the same as our calculated result, as
shown Fig. 3.14 Compound JTE-952 binds to the protein in a
DFG-out state with the bidentate hydrogen bonding network of
methoxy and benzyloxy and the backbone NH of Asp796. 4-
Cyclopropylbenzyl substituent binds to a lipophilic pocket which
is formed by the DFG-out conformational change of the protein.
In the hinge region, the backbone NH of Cys666 forms a
hydrogen bond to the C=O of the 2-picolyl–azetidine amide
substructure, which assumes the anti-planar conformation
between C=O vs. C=N in the pyridine. Also, the substituent at the
4-position on the pyridine ring is directed toward the outside of
References and notes
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Graphical Abstract
Discovery of a novel azetidine scaffold for
colony stimulating factor-1 receptor (CSF-
1R) Type II inhibitors by the use of docking
models
Leave this area blank for abstract info.
Kazutaka Ikegashira*, Taku Ikenogami, Takayuki Yamasaki, Yasunori Hase, Takayuki Yamaguchi, Koji
Inagaki, Satoki Doi, Tsuyoshi Adachi, Yoshihisa Koga, Hiromasa Hashimoto
O
O
HO
N
O
O
N
4a
CSF-1R IC50 = 9.1 nM

A novel series of azetidine scaffold were identified as
colony stimulating factor-1 receptor (CSF-1R) Type II
inhibitors.


Compound 4a showed high CSF-1R inhibitory
activity (IC50 = 9.1nM).
A co-crystal structure of an azetidine compound with
CSF-1R was obtained.